The broad long term goal of the PI's laboratory is to help define the mechanisms underlying the progression of various heart diseases to congestive heart failure (CHF). In the present proposal animal models mimic human desmin-related cardiomyopathy (DRC) and hypertensive heart disease will be respectively investigated. Although DRC is not a common heart disease but understanding its pathogenesis will shed lights on many common forms of heart disease, especially those with increased production of abnormal proteins in cardiomyocytes. DRC is the cardiac component of desmin-related myopathy (DRM) which is often caused by genetic mutations. DRM or DRC is characterized by aberrant protein aggregation in muscle cells and this aggregation appears to play a central role in DRC pathogenesis. Notably, abnormal protein aggregation in the form of amyloid oligomers was also observed in human CHF resulting from common forms of heart disease. Intracellular protein aggregation and proteolytic disturbance are recently observed also in pressure overloaded mouse hearts. Hence, pathogenic insights gained from studying DRC may provide critical information for understanding molecular pathogenesis of CHF resulting from common cardiovascular disease. The ubiquitin- proteasome system (UPS) is responsible for the degradation of most cellular proteins and thereby plays indispensible roles in intracellular protein quality control and the regulation of virtually all cellular functions. In the previous project period, we have successfully unveiled severe proteasome (psm) impairment by abnormal protein aggregation in DRC mouse hearts. Notably, psm dysfunction is also observed in animal models of many other cardiac disorders, including pressure overload cardiomyopathy. It has also been implicated in human CHF of most causes. However, the pathophysiological significance of psm dysfunction in the heart is virtually unknown and will be extremely important to be defined. Accordingly, we propose to test an overall hypothesis that the inadequacy in psm-mediated proteolysis plays an essential role in DRC and in pressure overload cardiomyopathy, by pursuing the following 4 Specific Aims: (1) To determine the sufficiency of perinatal or adult onset cardiomyocyte-restricted psm inhibition (CR-PSMI) to induce cardiomyopathy and its reversibility in mice;(2) To investigate the impact of moderate and severe CR-PSMI on the removal of bona fide normal and abnormal proteins in the heart and investigate the functional relationship between psm- mediated proteolysis and autophagy in cardiomyocytes in mice;(3) To determine the necessity of psm functional insufficiency in the pathogenesis of DRC in mice;and (4) To determine the role of psm dysfunction in pressure overload cardiac remodeling and failure in mice. PUBLIC HEALTH RELEVANCE: Congestive heart failure is the final common pathway of virtually all heart disease and is the most expensive single diagnosis in US health care. It is a highly lethal and disabling syndrome. Despite recent advances in its clinical management, it remains the leading cause of death in the US. This research project will help deepen our understanding on the molecular mechanisms underlying the progression of various heart diseases to congestive heart failure, which will ultimately facilitate the search for new measures to prevent or more effectively treat this common and yet life-threatening disorder.